In the era of PSA screening, the incidence of prostate cancer has increased more than two fold with a concomitant rise in the number of radical prostatectomies performed. However, there has been only a modest decrease in cause-specific mortality. Thus, we are subjecting many patients with biologically indolent cancers to the morbidities of prostate cancer treatments such as radical prostatectomy, brachytherapy, and external beam radiation therapy. One of the strongest predictors of clinically aggressive behavior is high Gleason grade. However, we do not understand at a molecular level what differentiates low grade from high grade cancers. Using a candidate gene approach, differences in DNA methylation patterns have been shown between benign prostate and prostate cancer. More importantly, our preliminary data indicate that there are extensive DNA methylation differences between low and high Gleason grade cancers. Therefore, we hypothesize that DNA methylation differences underlie biological differences between indolent and aggressive prostate cancer. In Aim 1, we will perform a genome-wide mapping of DNA methylation patterns in benign prostate, low grade, and high grade cancers to identify areas of hypo- and hyper- methylation. In aim 2, we will subsequently validate these differences in additional, independent cohorts of clinical specimens. The goal is to utilize methylation differences as biomarkers that can distinguish between indolent and aggressive forms of the disease. Ultimately, these discoveries will help us understand the fundamental biological differences between indolent and aggressive prostate cancer, identify new biomarkers to distinguish them, and provide therapeutic targets for effective treatments.